POSTERS12-myristate-13-acetate (PMA) causes the formation of vesicles of internalized Ntcp within 60 minutes with a corresponding reduction in bile salt uptake.Administration of the bile salt taurolithocholic acid-3 sulfate (TLCS) leads to a dose and time dependent increase in cell stress and cell death.However, induced retrieval of Ntcp, prior to application of TLCS, abolishes its adverse effects by reducing the number of apoptotic cells and preserving intact cell morphology.These processes were sensitive to the nonselective PKC inhibitor bisindolylmaleimide I (BIM I) and G ö6976, the selective inhibitor of classical (c) PKC. Conclusion:Our findings demonstrate for the first time the endocytosis of Ntcp mediated by cPKC, which leads to a reduced bile acid uptake.This mechanism protects hepatocytes from bile salt induced cell damage.

Invasive aspergillosis is one of the most threatening infections in immunocompromised patients of risk. The classical standard therapy of deep-seated mycoses--amphotericin B as monotherapy or in combination with 5-fluorocytosine--shows a response rate in aspergillosis of 55-60%. The new triazole compound itraconazole demonstrating a high in vitro activity against Aspergillus species was used in the recent years in several studies in the treatment of invasive aspergillosis. We report on our own experiences of itraconazole therapy in invasive aspergillosis with 20 patients suffering from well-known classical underlying diseases and factors of risk. Diagnosis was based on clinical symptomatology and was serologically and culturally proved. Special efforts were made for an early diagnosis according to clinical criteria. Therefore, in numerous cases clinical diagnosis was made several days prior to mycological confirmation, and antimycotic therapy could be started. The mean dosis administered was 400 mg itraconazole per day. With four patients no therapy response could be observed. In one patient a partial remission was obtained. In 15 patients aspergillosis was cured. In our patients the rate of complete remission, therefore, amounted to 75%. In evaluating 12 published studies on itraconazole therapy of invasive aspergillosis (including our own patients) a response rate of 63% (169 of 269 patients) could be calculated. Therefore, increasing experience is indicating that itraconazole therapy might be an alternative to classical amphotericin B therapy of invasive aspergillosis.

In a prospective study we examined the diagnostic ranking of CT and MR in 52 immunocompromised patients with nodular pulmonary lesions and clinical suspicion of invasive pulmonary aspergillosis (IPA). For early diagnosis of IPA (clinical symptoms having existed for less than 10 days) the CT halo sign proved highly sensitive and specific. MRT showed at this time a comparatively high sensitivity but only low specificity that could not be improved upon after Gd-DTPA. At a later stage of the aspergillosis infection (clinical symptoms manifested for more than 10 days) MR identified aspergillus-specific lesions with on-target characteristics (marked enhancement of margins after Gd-DTPA) or the so-called "reverse" target phenomenon (T2-weighted sequences). Such lesions were never seen in the early stage of the disease in patients with nodular pulmonary lesions of different aetiology (pseudomonal or staphylococcal pneumonia).

We report on the treatment of invasive aspergillosis with the new triazole antimycotic agent itraconazole. All 11 patients suffered from pulmonary invasive aspergillosis. Two patients also had cerebral aspergillosis; in one of these patients the paranasal sinuses were also invaded. Underlying diseases were acute lymphoblastic leukaemia (n = 3), acute myeloid leukaemia (n = 4); one patient underwent allogeneic bone marrow transplantation before he developed aspergillosis; another was transplanted after successful aspergillosis treatment, liver cirrhosis (n = 1), lung infarction after pulmonary embolism (n = 1), chronic bronchitis after pulmonary tuberculosis (n = 1) and AIDS (n = 1). In five cases initial diagnosis was established by means of mycological methods and clinical signs. In six patients invasive pulmonary aspergillosis was initially diagnosed due to the clinical criteria presented in this paper. Secondary mycological confirmation after onset of therapy was achieved in five out of these six patients. All of the patients initially responded to therapy. One female patient experienced a relapse of aspergillosis and died of cerebral involvement and relapsing leukaemia. Two further patients died due to underlying diseases (pulmonary embolism, relapsing leukaemia). Nine patients (82%) were cured of the mycosis, including the patient with cerebral involvement; two underwent surgical resection of residual pulmonary lesions. Itraconazole is a very effective drug for treatment of invasive aspergillosis. Therapeutic efficacy can be optimized by early diagnosis using clinical criteria and prompt start of treatment.

Die frühzeitige Anwendung einer antibiotischen Therapie mit einem Breitspektrum-Antibiotikum hat die Morbidität und Mortalität schwerer und langdauernder Zytopenien bei allogen oder autolog knochen-marktransplantierten Patienten deutlich vermindert. Ceftazidim zusammen mit einem Aminoglykosid, wie z.B. Netilmicin, hat sich als eine Kombination von niedriger oder gar vermeidbarer Toxizität eingeführt. Wir untersuchten Teicoplanin bei vermuteten grampositiven Infektionen nach ungenügendem Ansprechen auf die anfängliche Kombinationstherapie von Beta-Lactam-Antibiotika und Aminoglykosiden. Alle 16 in dieser Studie erfaßten Patienten wurden entweder allogen (acht Patienten) oder autolog (acht Patienten) transplantiert mit folgenden Grundkrankheiten: akute myeloische Leukämie (AML), Non-Hodgkin-Lymphom (NHL) oder anderen malignen Erkrankungen. Alle Patienten, die eine primäre Septikämie unbekannten Ursprungs entwickelten (15 Patienten) oder unter einer Katheter-bedingten Septikämie (ein Patient) litten, wurden mit 400 mg Teicoplanin behandelt. Die Verabreichung von Teicoplanin erfolgte einmal täglich intravenös in Kombination mit einem Cephalosporin und einem Aminoglykosid (Ceftazidim 2 g i.v., 3 ×/die, Netilmicin 400 mg, 1 ×/die). Alle behandelten Patienten sprachen auf diese Therapie an. 15 Patienten waren klinisch geheilt, ein Patient besserte sich unter dieser Therapie. Die Kombinationstherapie wurde gut vertragen, unerwünschte Arzneimittelwirkungen traten nicht auf. Wir konnten kein verzögertes Angehen des Knochenmarks oder eine Verlängerung der Thrombozytopenie unter dieser Behandlung im Vergleich zu anderen knochenmarktransplantierten Patienten, die diese antimikrobielle Behandlung nicht erhielten, feststellen. Unsere bisherigen Ergebnisse zeigen, daß Teicoplanin ein wirksames und gut verträgliches Antibiotikum für knochenmarktransplantierte Patienten ist, die primär nicht auf die Kombinationstherapie mit Beta-Laktam-Antibiotika und Aminoglykosiden ansprechen.

Gram-positive bacteria causing life-threatening septicaemia in neutropenic patients undergoing bone marrow transplantation represent a major transplantation-related complication. We therefore evaluated teicoplanin for suspected gram-positive infections after an inadequate response to initial empiric beta-lactams and aminoglycoside combination therapy. Eleven patients included in this regimen received an allogenic (five patients) or autologous (six patients) bone marrow transplant for acute myeloid leukemia (AML), Non-Hodgkin-Lymphoma (NHL, high grade) or other malignant diseases. All patients under study developing a primary septicaemia of unknown origin (15 patients) or a catheter-related septicaemia (one patient) were treated with teicoplanin, 400 mg i.v. once daily in combination with a cephalosporin and an aminoglycoside (ceftazidime 2 g i.v., t.i.d., and 400 mg netilmicin i.v., q.d.). Teicoplanin serum levels were monitored closely of all patients under investigation.All 16 patients responded to therapy, 15 patients were clinically cured, one patient improved under therapy. So far we have not observed any delayed take or prolonged neutropenia with this therapeutic regimen when compared to other bone marrow transplant patients, who did not receive this antimicrobial therapy. All patients tolerated this regimen well, adverse drug reactions did not occur.We conclude that teicoplanin is a potentially effective and safe antimicrobial agent in patients with life-threatening septicaemia after bone marrow transplantation and might be considered a useful, nontoxic agent treating infections not responding primarily to beta-lactams and aminoglycosides.

We are reporting on a 25 years old patient with acute myelogenous leukemia, who developed an acute graft-versus-host disease (GVHD) 43 days after allogeneic bone marrow transplantation (BMT). The clinical symptoms included exanthema, diarrhea and abdominal cramps. The patient was treated with cyclosporine A and prednisone and the clinical symptoms disappeared subsequently. At day 225 post BMT the patient became icteric as the clinical manifestation of chronic GVHD. We describe in this case report endoscopical and histological findings during the episodes of acute and chronic graft-versus-host disease. The results obtained by sigmoidoscopy and liver biopsy confirmed the clinical diagnosis. The clinical work up of patients with acute or/and chronic GVHD should also include sigmoidoscopy in order to verify this transplantation related complication.

The activity of dipeptidyl aminopeptidase IV was studied in the sera of 378 hospitalized patients. The mean activity of dipeptidyl aminopeptidase IV was elevated significantly in patients with neoplasmata and hepatitis, but not in patients with liver cirrhosis. Significant correlations (p less than 0.001) existed with gamma-glutamyl transferase, glutamate dehydrogenase, alkaline phosphatase and leucine aminopeptidase. A significant correlation with lactate dehydrogenase existed only in patients with neoplasmata. Principal component analysis, performed with aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, leucine aminopeptidase, lactate dehydrogenase and dipeptidyl aminopeptidase IV, revealed correlations between the activities of aspartate aminotransferase and alanine aminotransferase, and between alkaline phosphatase and leucine aminopeptidase, but neither dipeptidyl aminopeptidase IV nor lactate dehydrogenase showed any correlation with either of these two groups. In lectin affinity chromatography with concanavalin A and wheat germ lectin sepharose, serum dipeptidyl aminopeptidase IV from liver cirrhosis patients showed the same binding pattern as that from healthy subjects. The activity and glycosylation of dipeptidyl aminopeptidase IV in serum and hepatic plasma membranes was investigated in rats, following the induction of hepatitis with galactosamine. In the serum, dipeptidyl aminopeptidase IV activity was elevated as early as 6 h after galactosamine injection, and the elevated activity persisted until the 7th day. At the same time dipeptidyl aminopeptidase IV activity was also elevated in the hepatic plasma membrane. Ninety eight percent of hepatic dipeptidyl aminopeptidase IV bound to concanavalin A as well as to wheat germ lectin and this value was unchanged during hepatitis. In the serum of control rats, 90% of dipeptidyl aminopeptidase IV bound to concanavalin A but only 39% to wheat germ lectin.(ABSTRACT TRUNCATED AT 250 WORDS)

The activity of dipeptidyl aminopeptidase IV was studied in the sera of 378 hospitalized patients. The mean activity of dipeptidyl aminopeptidase IV was elevated significantly in patients with neoplasmata and hepatitis, but not in patients with liver cirrhosis. Significant correlations (p less than 0.001) existed with gamma-glutamyl transferase, glutamate dehydrogenase, alkaline phosphatase and leucine aminopeptidase. A significant correlation with lactate dehydrogenase existed only in patients with neoplasmata. Principal component analysis, performed with aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, leucine aminopeptidase, lactate dehydrogenase and dipeptidyl aminopeptidase IV, revealed correlations between the activities of aspartate aminotransferase and alanine aminotransferase, and between alkaline phosphatase and leucine aminopeptidase, but neither dipeptidyl aminopeptidase IV nor lactate dehydrogenase showed any correlation with either of these two groups. In lectin affinity chromatography with concanavalin A and wheat germ lectin sepharose, serum dipeptidyl aminopeptidase IV from liver cirrhosis patients showed the same binding pattern as that from healthy subjects. The activity and glycosylation of dipeptidyl aminopeptidase IV in serum and hepatic plasma membranes was investigated in rats, following the induction of hepatitis with galactosamine. In the serum, dipeptidyl aminopeptidase IV activity was elevated as early as 6 h after galactosamine injection, and the elevated activity persisted until the 7th day. At the same time dipeptidyl aminopeptidase IV activity was also elevated in the hepatic plasma membrane. Ninety eight percent of hepatic dipeptidyl aminopeptidase IV bound to concanavalin A as well as to wheat germ lectin and this value was unchanged during hepatitis. In the serum of control rats, 90% of dipeptidyl aminopeptidase IV bound to concanavalin A but only 39% to wheat germ lectin.(ABSTRACT TRUNCATED AT 250 WORDS)